Apoptosis, also known as programmed cell death, is an active process essential for normal development and functions of multicellular organisms. Typically, apoptosis involves isolated single cells and is characterized by DNA fragmentation, morphological changes of cells and nuclei including cell shrinkage, cell surface blebbing, exposure of phosphatidylserine on the cell surface, involution, contraction, chromatin condensation and fragmentation, and phagocytosis without cell infiltration or inflammation. See Honig and Rosenberg, Am. J. Med., 108:317-330 (2000). Dysregulation of apoptosis can lead to various diseases and disorders. It is now well-known that reduced apoptosis may contribute to tumorigenesis and formation of cancer. Thus, induction of tumor cell apoptosis can be an effective approach in treating cancer. In addition, stimulation of endothelial cell apoptosis may prevent tumor blood supply and cause tumor regression. See Dimmeler and Zeiher, Cir. Res., 87:434-439 (2000). Dysregulation of apoptosis is also an integral part of a wide range of autoimmune diseases and disorders. See Ravirajan et al., Int. Rev. Immunol., 18:563-589 (1999). In addition, many neurological disorders involve apoptosis. During adulthood, there is little normal neuronal cell death. However, neurological diseases, particularly neurodegenerative diseases are often associated with excessive neural cell death. See Honig and Rosenberg, Am. J. Med., 108:317-330 (2000). For example, Parkinson's disease is associated with the loss of substantia nigra pars compacta and sympathetic ganglia, while Alzheimer's disease is characterized with selective cell loss of entorhinal neurons, and hippocampal neurons, cortical neurons. See Honig and Rosenberg, Am. J. Med., 108:317-330 (2000). Apoptosis also plays an important role in osteoporotic disorders including, but not limited to, postmenopausal osteoporosis, involutional osteoporosis, and glucocorticoid-induced osteoporosis. See Weinstein, et al., Am. J. Med., 108:153-164 (2000). Apoptosis also has physiological significance in animal virus infection. See Kyama et al., Microbes and Infection, 2:1111-1117 (2000).
Degterev, Alexei, et al, “Identification of small-molecule inhibitors of interaction between the Bak BH3 domain and Bcl-xL,” Nat. Cell Biol., 3:173-182 (2001), disclose apoptosis promoting compounds of the formulas:
wherein X can be Br, Cl, or H, Y is Cl, or I, and Z is Br, or I. The compounds were shown via binding assay tests, to promote displacement of BH3 from a Bcl-XL fusion protein. The compounds were also shown to have apoptotic cytotoxicity when applied to Jurkat T lymphoma cells. The apoptotic cytotoxicity of the compounds quantitatively paralleled their in vitro Bcl-XL binding activities.
U.S. Pat. No. 6,284,783 discloses a method of inducing apoptosis in target cells of a subject by administering, to the subject a pharmaceutically effective amount of at least one compound of the formula:
wherein: R1 is hydrogen, C1-C12 alkyl, C1-C12 substituted alkyl, C3-C7 heterocycle, or C 3-C7 substituted heterocycle, R2 and R3 are independently H or C1-C12 alkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein following the administration of the compound of Formula I, the target cell is caused to undergo apoptosis.
U.S. Pat. No. 6,316,462 discloses a method of treating cancer in a patient by inducing apoptosis with (1) a farnesyl protein transferase inhibiting amount of a fused-ring tricyclic benzocycloheptapyridine and (2) an additional Ras signaling pathway inhibitor. The farnesyl protein transferase inhibitor has a formula:

Despite of recent success in designing and identifying compounds that affect apoptosis, there is a continuing search for compounds capable of modulating apoptosis, and effective in treating diseases and disorders.